Understanding

Clinical Trials
Developed by Sara Back, NP
Bronx-Lebanon Hospital Center

NY/VI AETC

Overview

Purpose of Research Studies

Classifications of Epidemiological Research
Basic Research Terminology
Features of Clinical Trials

Design/Protocol
Phases of a Study
Ethics
Protection of Participants

Contributions of Clinical Trials

Participating in a Trial
Conclusion & Take Home Message
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Overview to Research Studies

Why Do Research Studies?
To collect data on usual and unusual
events, conditions, & population groups
To test hypotheses formulated from
observations and/or intuition
Ultimately, to understand better ones
world and make sense of it
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Overview to Research Studies

Various types of research studies
Many classified as Epidemiological
Studies

Epidemiology often is defined as:

The study of the distribution of a disease or

condition in a population and the factors that
influence that distribution.
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Classifications of Research Studies:

Three Main Types
Observational Studies:
Groups are studied & contrasts made between groups
The observed data collected are analyzed
Analytic Studies:
Also called Experimental
Study the impact of a certain therapy
Ultimately the investigator controls factor being studied
Clinical Trial:
Considered the true experimental study
Gold Standard of clinical research
Often a prospective study that compares the effect and value
of an intervention against a control in human subjects
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Another Classification System

Non-directed Data Capture
Ex: Vital Statistics

Directed Data Capture & Hypothesis

Testing
Ex: Cohort Studies, Case Control Studies

Clinical Trials
Ex: Investigation of Treatment/Condition
Ex: Drug Trials
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The Different Study Designs

Case-control
Cohort
Case Reports
Case Series
Outcomes Based: Survey Research:
Quality of Life
Decision analysis
Economic Analysis

Questionnaires
Polls
Surveys

Meta Analyses
Survival Analysis
Randomized Clinical Trial
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Basic Research Terminology

Retrospective: Refers to time of data
collection
Prospective: Refers to time of data
collection
Case Control Study: Persons w/ disease
& those w/out are compared
Cohort Study: Persons w/ and/or w/out
disease are followed over time
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Terminology (Cont.)
Cross-sectional Study: Presence or
absence of exposure to possible risk factor
measured at one point in time. Prevalence
obtained.
Prevalence: The # of new cases and
existing cases during specified time period.
Incidence: The # of NEW cases per unit of
a population at risk for disease occurring
during stated time period.
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Historical Minute
First Clinical Trials

Clinical Trials have a long history even

if not acknowledged as Clinical trials
Formal record of clinical trials dates back
to the time of the Trialists:
Dr. Van Helmonts proposal for a therapeutic
trial of bloodletting for fevers [1628]
Dr. Linds, a ship surgeon, trial of oranges &
limes for scurvy [1747]
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Historical Minute
First Clinical Trials
Historical Highlights of Drug Trials

1909: Paul Ehrlich - Arsphenamine

1929: Alexander Fleming - Penicillin
1935: Gerhard Domagk - Sulfonamide
1944: Schatz/Bugie/Waksman Streptomycin
By 1950, the British Medical Res. Council
developed a systematic methodology for studying
& evaluating therapeutic interventions
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Core Components of Clinical Trials

Involve human subjects

Move forward in time
Most have a comparison CONTROL group
Must have method to measure intervention
Focus on unknowns: effect of medication
Must be done before medication is part of
standard of care
Conducted early in the development of
therapies
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Core Components of Clinical Trials

Must review existing scientific data &
build on that knowledge
Test a certain hypothesis
Study protocol must be built on sound &
ethical science
Control for any potential biases
Most study medications, procedures,
and/or other interventions
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The Possible World of Clinical

Trial Designs
Randomized/blinded trial
Randomized/double blinded trial
Non-randomized concurrent controlled
trial
Placebo trial
Historical controlled trial
Crossover Trial
Withdrawal trial
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Simplified
Randomized:
Schemes used to
assign participant to
one group
o

Ex: Every 3 gets higher

dose

Nonrandomized: All
with Hep. C = cases;
others = controls
Protocol: Study
design - instructions

Blinded: Participants
do not know if in
experimental or control
group
Double Blinded:
Participants AND staff
do not know group
assignment
Placebo: Inactive pill
w/ no therapeutic value
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Components of Clinical Trial Protocols

Investigating two or more conditions so
have two(+) groups
Ex: drug vs. placebo; medicine vs. surgery;
low dose vs. high dose

Specific inclusion/exclusion criteria

Sample size & power calculations
Plan re: potential biases
Plan re: handling of attrition/loss to
follow up
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Study Participant Recruitment

Identify eligible
participants
Explain study
Provide informed
consent
Reassess eligibility
Assign to one group

Participants should be told:

May have side effects
(adverse effects)
Time commitment
Benefits & risks
May withdraw at any time
Enrollment 100%
voluntary
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Phases of Clinical Trials

Most trials that involve new drugs go
through a series of steps:
#1: Experiments in the laboratory
#2: Once deemed safe, go through 1-4
phases

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Phases of Clinical Trials

Phase I: Small group [20-80] for 1st time to
evaluate safety, determine safe dosage range &
identify SE
Phase II: Rx/tx given to larger group [100300] to confirm effectiveness, monitor SE, &
further evaluate safety

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Phases of Clinical Trials (cont.)

Phase III: Rx/tx given to even larger group
[1,000-3,000] to fulfill all of Phase II objectives
& compare it to other commonly used txs &
collect data that will allow it to be used safely
Phase IV: Done after rx/tx has been marketed studies continue to test rx/tx to collect data
about effects in various populations & SE from
long term use.

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Summary of Phases I-III

# Subs. Length Purpose

% Drugs
Successfully
Tested

Phase I 20 100

Several
months

Mainly Safety

70%

Phase II Up to

Several
months2 yrs.

Short term
safety; mainly
effectiveness

33%

Phase
III

1-4 yrs.

Safety, dosage
& effectiveness

25-30%

several
100
100s
several
1000

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Ethics of Clinical Trials:

Protection of Participants
3 ethical principles guide clinical research:
Respect for Persons: Treatment of person
as autonomous
Beneficence: Issue re: potential conflict
between good of society vs. individual
Justice: Treatment of all fairly & all
equally share benefits & risks
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Ethical Norms of Clinical Trials

Sound study designs take into account:
Randomization or sharing of risks
Proper use of placebo
Processes to monitor safety of rx/tx
Competent investigators
Informed consent
Equitable selection of participants
Compensation for study related injuries
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Ethical Issues:
Protection of Human Subjects
Rely on integrity of Investigator but outside groups also
have oversight
Participants rights protected by Institutional Review
Boards [IRBs]
o

An IRB is defined as: "any board, committee or

other group formally designated by an institution to
review, to approve the initiation of, and to conduct
periodic review of biomedical research involving
human subjects"
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Human Subjects Protection

IRB responsible for such tasks:
Review research to ensure that potential
benefits outweigh risks
Develop and issue written procedures
Review research for risk/benefit analysis &
proper protection of subjects
Issue written notice of approval/disapproval to
the Investigator
Review and respond to proposed protocol
changes submitted by the Investigator
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Human Subjects Protection

IRB Responsibilities (continued):
Review reports of deaths, and serious
and unexpected adverse events received
from the Investigator
Conduct periodic continuing review of
the study, study risks, selection of
subjects, privacy of subjects,
confidentiality of data, and the consent
process
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Historical Minute:
Origin of IRBs & Human Subject Code
Attention to protecting participants began after
WWII w/ the Nuremberg Trials (1947)
Out of those trials, key points were codified

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Historical Minute:
10 Key Points

Voluntary informed consent

Experiment must be for the good of society, & results not obtainable
by other means

Experiment should be based upon prior animal studies

Physical & mental suffering & injury should be avoided

No expectation that death/disabling injury will occur from the
experiment
Risk vs. benefit
Protect subjects against injury, disability, or death
Only scientifically qualified persons to be involved
Subject can terminate her/his involvement

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Historical Minute:
Origin of IRBs & Human Subject Codes

Since 1947, additional subject protection

requirements developed & implemented
Latest additions: Year 2000 - President
Clinton & DHHS Secretary Shalala
announced additional study requirements
related to:
informed consent
training req. adverse events
conflict of interest civil monetary penalties
improved monitoring of Phase I & II trials

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Informed Consent:
A Part of Human Subject Protection
Objectives of Informed Consent
To Ensure:
Voluntariness
Comprehension
Information
To Demonstrate That:
Person freely gave consent to participate
Consent given by a competent person
Person has been given all information
Person knows this is research not treatment
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Components of Informed Consent

Must Include the Following Information:

Why research being done?
What researchers want to accomplish
What will be done and for how long
Risks & benefits of trial
Other treatments available
Can withdraw from trial whenever desire
Compensation for unexpected injuries
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Vulnerable Populations
Groups thought not to have autonomy to give informed
consent:
children
mentally impaired, individuals with dementia
Prisoners
OR
Who may be unduly influenced to participate:
students
subordinates
pregnant women (actually, the fetuses)
patients (care-giver vs. researcher)
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Vulnerable Populations
To safe guard these groups, special
requirements such as:
Only parent can consent for minor
Consents must be in subjects native lang.
Prisoners: only some types of research
allowed
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Inclusion in Clinical Trials

NIH Revitalization Act of 1993: Guidelines
that require inclusion of women &
minorities in clinical studies
New guidelines stipulate that:
o
o
o
o

Women & minorities are to be included in all

human subject research
They are to be included in Phase III trials to
allow sufficient power to note differences
Cost cannot be a barrier
Outreach activities must take place to include
& follow these groups
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Inclusion in Clinical Trials

Historically women were excluded if of
reproductive age (ages 18-45)
Fear of harm to potential unborn child
In essence, excluded MAJORITY of
women
New guidelines eliminates this stipulation

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Issues in Clinical Trials:

Use of Placebo Trials
On international realm, 1999 Declaration of Helsinki
revised to address use of placebos:
Placebos not ethical in virtually all studies that involve
diseases with PROVEN tx
Remain ethical in trials where no proven tx
Revisions due to controversy over use of placebos in
attempting to find easy/cheap way to reduce HIV
perinatal transmission
1998 study in Ivory Coast, Uganda, & Thailand:
HIV+ pregnant women given either placebo or
shorter course of AZT
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Participation in Clinical Trials

Why Some Participate:
Give back to society
Exhausted all other txs
Health care services
Payment & incentives
Support
Others??

Why Some Do Not?

Mistrust of studies
Do not want to be
guinea pig
Do not meet criteria
Cannot give up time for
study visits
Barriers: lang., distance

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Taking Part in Research Studies:

Questions to Ask

What is study about?

What are the goals?
Study sponsor?
Participant input into
protocols?
Inclusion criteria?
Benefits & risks

Is there an incentive?
How protected from
harm?
What is required: # study
visit & what occurs?
What happens after study
is over?
How results will be
disseminated?
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The Impact of Studies

Some clinical trials have been critical to
patient health & provision of health care
For instance:
o
o
o
o

Protocol 076: HIV perinatal transmission

1st trial of AZT
Various cancer treatments
Development of other HIV related
medications like PIs
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The Impact of Studies

Other clinical trials have not been as
successful for a variety of reasons:
Medications did not work as in
laboratory
Loss to Follow-Up of too many patients
Harmful substance
Unethical & poorly conducted study (Ex:
Tuskegee Study & recent Gene
Replacement Study)
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Conclusions &
Take Home Message
Clinical trials often yield important results that
affect health and well being
Must follow guidelines & protocol
Must ensure well-being of participant
Clinical trials are susceptible to human error
either on part of investigator or patient
Research is soft science

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